DESCRIPTION (Taken directly from the application) Extensive analysis has revealed that CFTR deficient mice do not develop the type of life threatening respiratory disease that characterizes human cystic fibrosis. This suggests that factors in addition to the loss of normal CFTR function may play a role in the pathogenesis of human CF. Two factors that we hypothesize may play such a role are mucus secretion and chloride secretion through channels other than CFTR. To test whether these factors due indeed play a role in the development of respiratory disease subsequent to loss of CFTR function, we will selectively alter chloride and mucus secretion in the airways of CFTR deficient mice. With regard to chloride secretion, we hypothesize that the damage to a particularly tissue caused by loss of CFTR function can be related to the extent to which the epithelium of that tissue is dependent on CFTR for chloride secretion. With regard to mucus secretion, we hypothesize that the damage caused by loss of CFTR function in a particular tissue can be correlated with the amount of mucin secreted by the epithelium in that tissue. In addition to testing these two hypotheses separately, we will also determine whether the pathological changes associated with loss of CFTR function may result from a strong reliance on CFTR for chloride secretion in combination with the secretion of relatively large amounts of mucus. The final aim of this application is to develop new techniques that will extend our ability to evaluate the role of particular gene products in the pathogenesis of CF in vivo. More specifically, we propose to develop a system that will allow us to modify the expression of genes in mouse airways in a tissue and developmentally specific manner. In addition to providing a better understanding of the pathogenesis of human CF, such a system should also aid in the identification of potential targets for therapeutic intervention in the disease.